TARDNA binding protein-43 (TDP-43) is a multifunctional DNA/RNA-binding factor that has been implicated to play a role in the regulation of the neuronal plasticity. Interestingly, TDP-43 has also been identified as the major constituent of the neuronal cytoplasmic inclusions (NCIs) characteristic of a range of neurodegenerative diseases including the frontotemporal lobar degeneration with ubiquitin-positive inclusions.(FTLD-U) and amyotrophic lateral sclerosis (ALS).
Biochemical analyses have revealed that TDP-43 is promiscuously modified/processed in the affected regions of the brains and spinal cords of the FTLD-U and ALS patients, respectively. In particular, TDP-43 derived polypeptides have been detected on. Western blots of the urea-soluble extracts from the pathological samples with TDP-43(+) UBIs, which include: 1) multiple species of high molecular weight, poly-ubiquitinated TDP-43; 2) phosphorylated TDP-43 migrating at ˜45 kDa; and 3) ˜25 kDa and 35 kDa C-terminal fragments of TDP-43. In addition, immunohistochemistry analysis of the pathological samples from FTLD-U and ALS patients has revealed the presence of disease cells with NCIs adjacent to TDP-43-depleted nuclei. The depletion of the nuclear TDP-43 and the formation of the UBIs have been suggested to cause loss-of-function of TDP-43 and cellular toxicity, thus leading to the pathogenesis of FTLD-U as well as ALS with the TDP-43(+) UBIs.
Using a Thy-1 promoter, Wils et al. (2010) has generated transgenic mice with overexpression of human TDP-43 in the neurons of the central nervous system in addition to other cell types in which the Thy-1 promoter is active, which include the thymocytes, myoblasts, epidermal cells and keratinocytes. Both degeneration of the cortical/spinal motor neurons associated with a spastic quadriplegia reminiscent of ALS and degeneration of the nonmotor cortical and subcortical neurons characteristic of FTLD were observed in their transgenic mice. Furthermore, cellular aggregates (NCIs and NIIs) containing ubiquitinated and phosphorylated TDP-43 as well as the 25 KDa TDP-43 fragments were detected in association with the disease development and progression of these human TDP-43 overexpressing transgenic mice.
Despite the rapidly accumulating data on the molecular and cellular properties of TDP-43 in relation to the formation TDP-43(+) NCIs or UBIs, a causative role of TDP-43 in the pathogenesis of FTLD-U remains undefined.
A previously unaddressed need exists in the art to address the aforementioned deficiencies and inadequacies, especially in connection with the roles of TDP-43 in neurodegenerative diseases.